The citation of references herein shall not be construed as an admission that such is prior art to the present invention.
A large array of human melanoma-associated antigens (MAA) has been identified and used in various immunization strategies to treat cancer patients. However, despite significant induction of tumor-specific T cells (Coulie and van der Bruggen, 2003; Rosenberg, 2004), the therapeutic efficacy of these approaches has been suboptimal, indicating a need for improving current strategies. Possible explanations for failure (Loose and Van de Wiele, 2009) include malignant cells producing immunosuppressive cytokines (IL-10, TGFβ, IL-6 and M-CSF), prostaglandins and vascular endothelial growth factor, thereby skewing the immune response towards type-2 or regulatory T cells and deleteriously modulating the differentiation, maturation and function of antigen presenting cells (APCs). Furthermore, malignant cells that chronically stimulate infiltrating T cells can actively exhaust and eliminate T cells through expression of molecules such as FasL, PDL-1 or RCAS 1. Finally, due to immune pressure, immunoresistant tumor cell variants emerge through selection of mutants with reduced antigenicity. This can affect the expression/function of molecules implicated in antigen processing and presentation or the expression of tumor antigens themselves (Hirohashi et al., 2009; Yee et al., 2000).
A way to circumvent this latter limitation would be to vaccinate against immunogenic proteins whose expression is critical for tumor growth and/or invasiveness. The matrix metalloproteinase-2 (MMP-2), overexpressed in many tumors including melanoma, may be such an antigen. MMP-2 is a proteolytic enzyme that degrades numerous components of extracellular matrix such as collagens, laminin or fibronectin and contributes to cell migration by clearing the surrounding extracellular matrix and basement membrane barriers. MMP-2 over-expression has been associated with tumor progression. Indeed, MMP-2 modulates various oncogenic processes such as angiogenesis (Brooks et al., 1998; Itoh et al., 1998) and tumor dissemination (Kessenbrock et al., 2010; Liotta et al., 1980; Westermarck and Kahari, 1999).
The present inventors previously identified MMP-2 as a novel melanoma-associated antigen (MAA) recognized by HLA-A*0201-restricted CD8+ tumor infiltrating lymphocytes (TILs) (Godefroy et al., 2005). Because MMP-2 activity is critical for melanoma progression, MMP-2 is a promising tumor antigen to target in immunotherapy against malignant melanoma. Accordingly, several patients administered CD8+ T cells that recognize this epitope among others have remained tumor-free up to 15 years after treatment (Godefroy et al., 2005; Khammari et al., 2007).